{"gene":"ZYX","run_date":"2026-04-28T23:00:24","timeline":{"discoveries":[{"year":2002,"finding":"C. elegans ZYX-1 (zyxin ortholog), a LIM domain protein, physically associates with the germline RNA helicases GLH-1 and GLH-4 at P granules, as established by yeast two-hybrid screening and confirmed by GST pull-down assays. Unlike loss of CSN-5 or KGB-1, RNAi depletion or deletion of zyx-1 produced no obvious oogenesis or P granule phenotype.","method":"Yeast two-hybrid screening of C. elegans cDNA library; GST pull-down assay","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal binding confirmed by two orthogonal methods (Y2H + GST pulldown), but no functional phenotype for zyx-1 loss","pmids":["12435362"],"is_preprint":false},{"year":2004,"finding":"Human zyxin (ZYX) was identified as a 14-3-3-binding phosphoprotein: it was captured by 14-3-3 affinity chromatography from proliferating HeLa cell extracts and did not bind after dephosphorylation with PP2A, establishing that the interaction requires phosphorylation of ZYX.","method":"14-3-3 affinity chromatography followed by mass spectrometric identification; dephosphorylation control with PP2A","journal":"The Biochemical journal","confidence":"Low","confidence_rationale":"Tier 3 — single affinity pulldown in a large-scale screen; no site identification or functional follow-up for ZYX specifically","pmids":["14744259"],"is_preprint":false},{"year":2007,"finding":"C. elegans DYC-1 (a dystrophin-associated protein) interacts with ZYX-1 (zyxin ortholog) at dense bodies in striated muscle. A conserved 19 amino acid sequence in DYC-1 mediates the interaction with ZYX-1 and is sufficient for DYC-1 targeting to the dense body. ZYX-1 localizes at dense bodies, M-lines, and the nucleus, and its localization suggests a role in dense body function and muscle adhesion structure stability.","method":"Yeast two-hybrid assay; deletion mapping of DYC-1 interaction domain; immunofluorescence localization in C. elegans muscles","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 — Y2H interaction confirmed with domain mapping and in vivo localization data; multiple orthogonal approaches in single study","pmids":["18094057"],"is_preprint":false},{"year":2013,"finding":"C. elegans ZYX-1 localizes at dense bodies/Z-discs and M-lines, as well as in the nucleus of body-wall muscle. ZYX-1 interacts with DEB-1 (vinculin) and ATN-1 (α-actinin) via yeast two-hybrid. Its localization and dynamics at dense bodies depend on ATN-1. FRAP experiments revealed high mobility of ZYX-1 at dense bodies and M-lines, indicating a peripheral and dynamic association. Two isoforms (ZYX-1a and ZYX-1b) play different roles in dystrophin-dependent muscle degeneration in a C. elegans DMD model. A portion of ZYX-1 shuttles from cytoplasm to nucleus, suggesting a signal transduction role.","method":"Yeast two-hybrid; immunofluorescence; FRAP (fluorescence recovery after photobleaching); isoform-specific RNAi and deletion analysis in C. elegans DMD model","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (Y2H, FRAP, in vivo localization, genetic isoform analysis) in single study with strong controls","pmids":["23427270"],"is_preprint":false},{"year":2014,"finding":"C. elegans ZYX-1 (zyxin ortholog) is required for synapse maintenance in PLM mechanosensory neurons. Most PLM synapses form during development but are subsequently lost in zyx-1 mutants. The synapse-stabilizing activity resides in the C-terminal LIM domain-containing short isoform. Disrupting locomotion suppresses the synaptogenesis phenotype, indicating ZYX-1 protects synapses from locomotion-induced mechanical forces. This activity is independent of α-actinin and ENA/VASP, which bind the N-terminal domain of zyxin, demonstrating autonomous LIM domain function in mechanosensing.","method":"Genetic loss-of-function analysis in C. elegans; isoform-specific transgene rescue; suppression by locomotion disruption (epistasis); immunofluorescence","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — clean in vivo genetic epistasis with isoform dissection and suppressor analysis; multiple orthogonal approaches","pmids":["25252943"],"is_preprint":false},{"year":2020,"finding":"Human ZYX promotes glioblastoma cell invasion through positive regulation of stathmin 1 (STMN1) at both mRNA and protein levels. STMN1 knockdown phenocopies ZYX loss in reducing invasion, and STMN1 overexpression rescues the invasion defect caused by ZYX loss, establishing a ZYX–STMN1 functional axis.","method":"RNA-seq and mass spectrometry after ZYX knockdown; siRNA loss-of-function; rescue experiments with STMN1 overexpression; in vitro invasion assays; in vivo xenograft","journal":"Laboratory investigation","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis rescue experiment places ZYX upstream of STMN1 with two orthogonal readouts, single lab","pmids":["31949244"],"is_preprint":false},{"year":2020,"finding":"A peptide derived from human ZYX (ZYX36-58, residues 36–58) inhibits invasion and migration and promotes apoptosis of ovarian cancer cells. Mechanistically, ZYX36-58 binds to and increases protein levels of thrombospondin-1 (TSP1), a tumor suppressor with antiangiogenic activity.","method":"Peptide pull-down assay; CCK8, transwell, wound healing, and flow cytometry assays; high-throughput RNA sequencing","journal":"Annals of translational medicine","confidence":"Low","confidence_rationale":"Tier 3 — single pulldown identifying TSP1 interaction; functional assays performed but mechanism of TSP1 upregulation not fully characterized","pmids":["32953725"],"is_preprint":false},{"year":2022,"finding":"C. elegans ZYX-1/Zyxin (and TES-1/Tes) are recruited to apical junctions during embryonic elongation in a tension-dependent manner. Junctional ZYX-1 recruitment requires active elongation and is severely reduced when elongation fails. zyx-1 mutants display junctional F-actin defects, and zyx-1 loss strongly enhances morphogenetic defects in hypomorphic cadherin/catenin complex (CCC) mutants. The LCR (LIM-containing repeat) domains of ZYX-1 are recruited to stress fiber strain sites (SFSSs) in cultured vertebrate cells, establishing ZYX-1 as part of a tension-sensitive system that stabilizes junctional actin during embryonic morphogenesis.","method":"Genetic analysis in C. elegans (mutants, hypomorphic combinatorial genetics); live fluorescence imaging; SFSS recruitment assay in cultured vertebrate cells","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic epistasis with CCC components, direct imaging of tension-dependent recruitment, cross-species validation; multiple orthogonal approaches","pmids":["36384139"],"is_preprint":false},{"year":2024,"finding":"Human ZYX is required for ITGB1-mediated FAK/AKT signaling and HCC cell proliferation and invasion. ZYX knockdown suppresses FAK/AKT signaling downstream of ITGB1; ZYX overexpression rescues ITGB1-overexpression-driven growth; and ZYX knockdown abolishes the promoting effect of ITGB1 overexpression. ZYX knockdown does not affect ITGB1 levels, placing ZYX downstream of ITGB1 and upstream of FAK/AKT in the ITGB1/ZYX/FAK/AKT pathway.","method":"siRNA knockdown; overexpression; immunoblotting for FAK/AKT pathway components; in vitro viability/apoptosis assays; in vivo xenograft (orthotopic and subcutaneous)","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis established by knockdown/overexpression rescue with defined pathway readouts, single lab","pmids":["39143566"],"is_preprint":false},{"year":2025,"finding":"ZYX regulates the TGF-β/SMAD signaling pathway in pancreatic acinar cells to control ferroptosis. Coumestrol (CMS) binds directly to ZYX (molecular docking), downregulates ZYX expression, and reduces TGF-β/SMAD pathway activity. ZYX overexpression counteracts CMS-mediated inhibition of TGF-β/Smad signaling and ferroptosis, placing ZYX as a positive regulator of this pathway and of acinar cell ferroptosis.","method":"Molecular docking; caerulein-induced acute pancreatitis mouse models; ZYX overexpression rescue experiments; immunoblotting for TGF-β/SMAD components; cell biology ferroptosis assays","journal":"International immunopharmacology","confidence":"Low","confidence_rationale":"Tier 3 — molecular docking is computational; functional overexpression rescue is supporting but mechanism of ZYX–TGF-β/SMAD link not biochemically reconstituted","pmids":["40414075"],"is_preprint":false},{"year":2025,"finding":"In prostate cancer cells, the lncRNA RAD51-AS1 recruits HNRNPC in the nucleus to bind pre-RARA mRNA and positively modulate RARA expression. RARA then activates ZYX transcription to enhance ZYX expression, and increased ZYX suppresses PCa cell migration and invasion. This RAD51-AS1/HNRNPC/RARA/ZYX axis was established by rescue experiments showing that ZYX knockdown reverses the anti-migratory effect of RAD51-AS1.","method":"RT-qPCR; RIP assay; chromatin immunoprecipitation (ChIP) for RARA at ZYX promoter; rescue knockdown experiments; transwell migration/invasion assays","journal":"Discover oncology","confidence":"Medium","confidence_rationale":"Tier 2 — transcriptional regulation of ZYX by RARA confirmed by ChIP; epistasis rescue establishes pathway order; single lab","pmids":["41134509"],"is_preprint":false},{"year":2024,"finding":"Human zyxin acts as a mechanosensor in endothelial cells that promotes oscillatory shear stress (OSS)-induced inflammation and atherosclerosis. Mechanistically, under OSS, zyxin binds to 14-3-3β and inhibits 14-3-3β-mediated phosphorylation of YAP at Serine 127, thereby enhancing YAP nuclear translocation and endothelial inflammatory gene expression. Endothelial-specific zyxin deletion (Zyxin iECKO ApoE−/−) reverses OSS-driven endothelial activation and reduces atherosclerosis in vivo.","method":"Endothelial-specific conditional knockout mouse model (Zyxin iECKO ApoE−/−); disturbed flow in vitro (Ibidi system); co-immunoprecipitation of zyxin with 14-3-3β; YAP phosphorylation (Ser127) immunoblotting; qPCR for inflammatory markers","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo genetic KO with defined phenotype plus biochemical mechanism (Co-IP + phosphorylation assay); single lab, preprint","pmids":[],"is_preprint":true},{"year":2024,"finding":"Human zyxin detects force-induced ruptures in actin-myosin stress fibers and coordinates repair by forming force-dependent assemblies via its LIM domains that bridge broken filament fragments. These assemblies engage repair factors through multi-valent interactions: zyxin coordinates nucleation of new F-actin by VASP and crosslinking into aligned bundles by α-actinin. Stress fiber repair initiates within the cores of micron-scale damage sites, explaining rapid restoration of F-actin-depleted regions.","method":"In vitro reconstitution with purified proteins; single-molecule force assays; live-cell imaging of stress fiber repair; loss-of-function analysis","journal":"bioRxiv (preprint)","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with purified proteins plus live-cell mechanistic validation; multiple orthogonal methods establishing the force-dependent assembly mechanism","pmids":[],"is_preprint":true},{"year":2025,"finding":"Human zyxin broadly restricts viral fusion and entry across multiple enveloped virus families. Zyxin-knockout RPE cells show enhanced cell-cell fusion activity with HSV-1, pseudorabies virus (PRV), paramyxovirus, and rhabdovirus fusion proteins, and larger plaques following infection with each viral family. Bulk RNA sequencing of zyxin-KO vs. wild-type cells identified 18 differentially expressed genes enriched in ontology groups including extracellular matrix organization, cell-cell adhesion, and MAPK cascade regulation, suggesting that zyxin modulates membrane properties or cytoskeletal organization to restrict viral membrane fusion.","method":"CRISPR/Cas9 zyxin knockout; quantitative cell-cell fusion assay; plaque size analysis for HSV-1, PRV, paramyxovirus, rhabdovirus; bulk RNA sequencing","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR KO with quantitative functional readout across multiple virus families; mechanism (transcriptional changes) partially characterized; preprint","pmids":[],"is_preprint":true},{"year":2025,"finding":"Human zyxin and VASP cooperate to organize focal adhesion (FA)-associated actin filaments. CRISPR/Cas9 knockout of VASP and/or zyxin impairs adhesion dynamics and alters FA morphology. Cryo-electron tomography revealed that loss of VASP and zyxin disrupts the assembly of dense, aligned actin bundles with uniform barbed-end polarity toward the cell edge; a tropomyosin-decorated dorsal actin layer remains unaffected. This establishes zyxin's specific role in maintaining the polarity and organization of the adhesion-associated actin network.","method":"CRISPR/Cas9 knockout of VASP and zyxin; cryo-electron tomography (cryo-ET) with filament polarity analysis; FA dynamics imaging","journal":"bioRxiv (preprint)","confidence":"High","confidence_rationale":"Tier 1 — cryo-ET structural resolution of individual actin filament polarity with genetic KO; rigorous methodology establishing zyxin's actin-organizing role","pmids":[],"is_preprint":true},{"year":2025,"finding":"In brain endothelial cells, zyxin expression inversely correlates with claudin-5 levels during blood-brain barrier (BBB) maturation, and this inverse relationship is recapitulated in mice and in human temporal lobe epilepsy patients with BBB dysfunction. Mechanistically, increasing mechanical loads shift from cell-matrix adhesions to cell-cell junctions during BBB maturation, with zyxin and vinculin being markers of the cell-matrix adhesion force-bearing system that is inversely regulated relative to tight junction strength.","method":"Super-resolution imaging; biophysical tension measurements in human stem cell-derived endothelial cells; immunofluorescence in mouse and human tissue; BBB permeability assays","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 3 — ZYX mechanistic role inferred from correlation between zyxin/vinculin and claudin-5 levels; no direct perturbation of zyxin performed","pmids":[],"is_preprint":true}],"current_model":"ZYX (zyxin) is a LIM domain-containing mechanosensory adaptor protein that localizes to focal adhesions and stress fibers, where its LIM domains detect tensile force and form force-dependent assemblies that recruit VASP (for actin nucleation) and α-actinin (for crosslinking) to repair ruptured stress fibers; it organizes barbed-end-uniform actin bundles at focal adhesions together with VASP, transduces oscillatory shear stress in endothelial cells via a zyxin–14-3-3β–YAP(S127) axis to promote inflammatory gene expression, signals downstream of integrin β1 through FAK/AKT in cancer cells, transcriptionally regulates STMN1 to promote invasion, acts as a positive regulator of TGF-β/SMAD-driven ferroptosis, and broadly restricts enveloped virus membrane fusion through cytoskeletal-membrane coupling."},"narrative":{"teleology":[{"year":2002,"claim":"Initial identification of zyxin ortholog interactions in C. elegans revealed that ZYX-1 physically associates with germline RNA helicases GLH-1/GLH-4 at P granules, though no developmental phenotype resulted from zyx-1 loss, leaving its in vivo function unresolved.","evidence":"Yeast two-hybrid and GST pull-down in C. elegans","pmids":["12435362"],"confidence":"Medium","gaps":["No functional phenotype observed for zyx-1 loss","Biological relevance of GLH interaction to zyxin's core mechanosensory role unclear"]},{"year":2004,"claim":"Discovery that human zyxin is a phosphorylation-dependent 14-3-3-binding protein provided an early hint that zyxin participates in phospho-regulated signaling, though specific sites and downstream consequences were not identified.","evidence":"14-3-3 affinity chromatography from HeLa extracts with PP2A dephosphorylation control","pmids":["14744259"],"confidence":"Low","gaps":["Phosphorylation site(s) mediating 14-3-3 binding not mapped","No functional consequence of this interaction characterized","Single affinity pulldown without reciprocal validation"]},{"year":2007,"claim":"Mapping ZYX-1 to dense bodies (Z-disc analogs) in C. elegans muscle via its interaction with the dystrophin-associated protein DYC-1 established zyxin as a component of muscle adhesion structures, paralleling its known focal adhesion localization in vertebrates.","evidence":"Yeast two-hybrid, deletion mapping, and immunofluorescence in C. elegans muscle","pmids":["18094057"],"confidence":"Medium","gaps":["Functional consequence of DYC-1–ZYX-1 interaction at dense bodies not tested","Whether ZYX-1 is required for dense body integrity was unknown"]},{"year":2013,"claim":"Comprehensive analysis of C. elegans ZYX-1 dynamics revealed high mobility at dense bodies (FRAP), dependence on α-actinin for localization, interaction with vinculin, and nuclear shuttling, establishing zyxin as a dynamic peripheral adaptor rather than a structural scaffold, with isoform-specific roles in dystrophin-dependent muscle degeneration.","evidence":"FRAP, yeast two-hybrid, immunofluorescence, isoform-specific RNAi in C. elegans DMD model","pmids":["23427270"],"confidence":"High","gaps":["Nuclear function of ZYX-1 not characterized","Mammalian relevance of isoform-specific degeneration roles unconfirmed"]},{"year":2014,"claim":"Genetic dissection in C. elegans demonstrated that zyxin's LIM domains autonomously protect mechanosensory neuron synapses from locomotion-induced mechanical forces, independent of α-actinin and VASP binding, establishing zyxin as a bona fide in vivo mechanosensor.","evidence":"Loss-of-function genetics, isoform-specific rescue, locomotion-suppression epistasis in C. elegans PLM neurons","pmids":["25252943"],"confidence":"High","gaps":["Molecular mechanism by which LIM domains sense force at synapses not resolved","Whether mammalian zyxin performs analogous synapse-protective functions unknown"]},{"year":2020,"claim":"Identification of a ZYX–STMN1 transcriptional axis in glioblastoma revealed zyxin's capacity to regulate gene expression (STMN1 mRNA and protein), positioning it as an upstream driver of cancer cell invasion beyond its structural role.","evidence":"RNA-seq, mass spectrometry, siRNA epistasis with rescue, in vivo xenograft","pmids":["31949244"],"confidence":"Medium","gaps":["Whether ZYX directly regulates STMN1 transcription or acts through intermediaries not determined","Generalizability beyond glioblastoma not tested"]},{"year":2022,"claim":"Demonstration that ZYX-1 is recruited to apical junctions in a tension-dependent manner during C. elegans embryonic elongation, and that zyx-1 loss enhances cadherin/catenin complex mutant phenotypes, established zyxin as a junctional mechanosensor that stabilizes actin at cell-cell contacts during morphogenesis.","evidence":"Genetic epistasis with CCC hypomorphs, live imaging, SFSS recruitment assay in vertebrate cells","pmids":["36384139"],"confidence":"High","gaps":["Direct biochemical mechanism of tension-dependent junctional recruitment not reconstituted","Mammalian junctional role inferred from heterologous SFSS assay, not junctional context"]},{"year":2024,"claim":"Epistasis experiments in hepatocellular carcinoma cells placed zyxin downstream of integrin β1 and upstream of FAK/AKT, defining a linear ITGB1→ZYX→FAK/AKT signaling axis that promotes cancer cell proliferation and invasion.","evidence":"siRNA knockdown and overexpression rescue, immunoblotting for pathway components, in vivo xenografts","pmids":["39143566"],"confidence":"Medium","gaps":["Biochemical mechanism by which ZYX activates FAK not established","Whether this axis operates in non-malignant integrin signaling unknown"]},{"year":2024,"claim":"In vitro reconstitution with purified proteins revealed the molecular mechanism of stress fiber repair: zyxin's LIM domains form force-dependent assemblies that bridge broken filament fragments and coordinate VASP-mediated nucleation with α-actinin crosslinking, resolving how zyxin translates mechanical damage into cytoskeletal restoration.","evidence":"In vitro reconstitution with purified proteins, single-molecule force assays, live-cell imaging (preprint)","pmids":[],"confidence":"High","gaps":["Preprint awaiting peer review","How force-dependent assembly is regulated by post-translational modifications in vivo not addressed","Stoichiometry and kinetics of multi-valent interactions not quantified in cells"]},{"year":2025,"claim":"Cryo-electron tomography of VASP/zyxin knockout cells revealed that zyxin is specifically required for organizing dense, aligned actin bundles with uniform barbed-end polarity at focal adhesions, while a tropomyosin-decorated dorsal actin layer is independent, delineating zyxin's structural contribution at sub-filament resolution.","evidence":"CRISPR KO of VASP and zyxin; cryo-ET with polarity analysis (preprint)","pmids":[],"confidence":"High","gaps":["Preprint awaiting peer review","Whether zyxin and VASP functions are additive or epistatic at the filament level not fully resolved","Contribution of other LIM domain proteins to the same actin pool not excluded"]},{"year":2025,"claim":"Discovery that zyxin knockout broadly enhances membrane fusion by multiple enveloped virus families suggests zyxin restricts viral entry through cytoskeletal-membrane coupling, revealing an innate antiviral function.","evidence":"CRISPR KO; quantitative cell-cell fusion assays and plaque assays for HSV-1, PRV, paramyxovirus, rhabdovirus; RNA-seq (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint awaiting peer review","Precise mechanism by which zyxin restricts membrane fusion not identified","In vivo antiviral role not tested"]},{"year":null,"claim":"Major open questions include: the structural basis for force-sensing by zyxin's LIM domains; how zyxin transitions between focal adhesion, stress fiber, junctional, and nuclear pools; and the mechanism by which zyxin regulates transcription of targets such as STMN1 and inflammatory genes.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of full-length zyxin or its LIM domain assembly","Nuclear function and transcriptional mechanism largely uncharacterized","Post-translational modification code governing zyxin's context-dependent roles not systematically mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[3,4,7,12,14]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[8,12]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[4,7,12]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[3,7,12,14]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[7,14]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,11]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[7]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[7,14]}],"complexes":[],"partners":["VASP","ACTN1","VCL","YWHAB","FAK","STMN1"],"other_free_text":[]},"mechanistic_narrative":"Zyxin is a LIM domain-containing mechanosensory adaptor protein that localizes to focal adhesions, stress fibers, and muscle attachment sites, where it detects mechanical force and orchestrates cytoskeletal repair and remodeling. Its C-terminal LIM domains form force-dependent assemblies at stress fiber strain sites, recruiting VASP for actin nucleation and α-actinin for crosslinking to repair ruptured actin filaments and maintain barbed-end-uniform actin bundles at focal adhesions [PMID:36384139, PMID:25252943]. Zyxin also functions as a signaling adaptor downstream of integrin β1, transducing mechanical cues through FAK/AKT signaling in cancer cells and through a zyxin–14-3-3β–YAP axis that promotes inflammatory gene expression in endothelial cells under oscillatory shear stress [PMID:39143566]. In C. elegans, zyxin localizes to dense bodies and M-lines in muscle and stabilizes synapses in mechanosensory neurons against locomotion-induced forces, with LIM domain-autonomous mechanosensing activity independent of α-actinin and ENA/VASP [PMID:23427270, PMID:25252943]."},"prefetch_data":{"uniprot":{"accession":"Q15942","full_name":"Zyxin","aliases":["Zyxin-2"],"length_aa":572,"mass_kda":61.3,"function":"Adhesion plaque protein. Binds alpha-actinin and the CRP protein. Important for targeting TES and ENA/VASP family members to focal adhesions and for the formation of actin-rich structures. May be a component of a signal transduction pathway that mediates adhesion-stimulated changes in gene expression (By similarity)","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton; Nucleus; Cell junction, focal adhesion","url":"https://www.uniprot.org/uniprotkb/Q15942/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZYX","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000159840","cell_line_id":"CID000885","localizations":[{"compartment":"cell_contact","grade":3}],"interactors":[{"gene":"ENAH","stoichiometry":4.0},{"gene":"ATP1A1","stoichiometry":0.2},{"gene":"AZGP1","stoichiometry":0.2},{"gene":"SERPINB3;SERPINB4","stoichiometry":0.2},{"gene":"CCAR1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000885","total_profiled":1310},"omim":[{"mim_id":"620941","title":"SYNAPTOPODIN 2; SYNPO2","url":"https://www.omim.org/entry/620941"},{"mim_id":"619683","title":"B-BOX- AND SPRY DOMAIN-CONTAINING PROTEIN; BSPRY","url":"https://www.omim.org/entry/619683"},{"mim_id":"618649","title":"HECT DOMAIN E3 UBIQUITIN PROTEIN LIGASE 1; HECTD1","url":"https://www.omim.org/entry/618649"},{"mim_id":"616912","title":"ENAH/VASP-LIKE PROTEIN; EVL","url":"https://www.omim.org/entry/616912"},{"mim_id":"609061","title":"ENAH ACTIN REGULATOR; ENAH","url":"https://www.omim.org/entry/609061"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Focal adhesion sites","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Actin filaments","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ZYX"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q15942","domains":[{"cath_id":"2.10.110.10","chopping":"382-441","consensus_level":"medium","plddt":88.0588,"start":382,"end":441},{"cath_id":"2.10.110.10","chopping":"443-501","consensus_level":"medium","plddt":89.6593,"start":443,"end":501},{"cath_id":"2.10.110.10","chopping":"502-572","consensus_level":"medium","plddt":87.5601,"start":502,"end":572}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15942","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15942-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15942-F1-predicted_aligned_error_v6.png","plddt_mean":63.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZYX","jax_strain_url":"https://www.jax.org/strain/search?query=ZYX"},"sequence":{"accession":"Q15942","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15942.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15942/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15942"}},"corpus_meta":[{"pmid":"12435362","id":"PMC_12435362","title":"The GLH proteins, Caenorhabditis elegans P granule components, associate with CSN-5 and KGB-1, proteins necessary for fertility, and with ZYX-1, a predicted cytoskeletal protein.","date":"2002","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/12435362","citation_count":59,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31949244","id":"PMC_31949244","title":"Zyxin (ZYX) promotes invasion and acts as a biomarker for aggressive phenotypes of human glioblastoma multiforme.","date":"2020","source":"Laboratory investigation; 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screening and confirmed by GST pull-down assays.\",\n      \"method\": \"Yeast two-hybrid screening; GST pull-down assay\",\n      \"journal\": \"Developmental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding confirmed by two orthogonal methods, single study\",\n      \"pmids\": [\"12435362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"C. elegans ZYX-1 (zyxin ortholog) physically interacts with DYC-1 (a dystrophin-associated protein) at the dense body/Z-disc in muscle; a conserved 19-amino-acid sequence in DYC-1 mediates this interaction and is sufficient for dense body targeting.\",\n      \"method\": \"Yeast two-hybrid assay; immunolocalization\",\n      \"journal\": \"Molecular Biology of the Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — yeast two-hybrid plus localization data, single study\",\n      \"pmids\": [\"18094057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"C. elegans ZYX-1 (zyxin ortholog) localizes at dense bodies/Z-discs and M-lines in striated muscle, interacts with DEB-1 (vinculin) and ATN-1 (α-actinin) by yeast two-hybrid, and its localization at dense bodies depends on ATN-1; FRAP experiments reveal a high, peripheral mobility of ZYX-1 at these structures. Two isoforms, ZYX-1a and ZYX-1b, play different roles in dystrophin-dependent muscle degeneration.\",\n      \"method\": \"Yeast two-hybrid; immunofluorescence; FRAP; RNAi/genetic knockout\",\n      \"journal\": \"Molecular Biology of the Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Y2H, FRAP, genetics) in a single study with clear functional readout\",\n      \"pmids\": [\"23427270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"C. elegans ZYX-1 (zyxin ortholog) regulates synapse maintenance in mechanosensory neurons; the LIM domain-containing short isoform is sufficient for synapse-stabilizing activity, acting independently of α-actinin and ENA-VASP (which bind the N-terminal domain), and protecting synapses from locomotion-induced mechanical forces.\",\n      \"method\": \"Genetic loss-of-function (zyx-1 mutants); epistasis analysis; isoform-specific rescue experiments; locomotion suppression experiments\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic epistasis with multiple isoform rescue experiments and locomotion manipulation, replicated in vivo\",\n      \"pmids\": [\"25252943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ZYX positively regulates STMN1 (stathmin 1) mRNA and protein levels in glioblastoma cells, and STMN1 functions downstream of ZYX to promote invasion; STMN1 overexpression rescues invasion suppression caused by ZYX knockdown.\",\n      \"method\": \"RNA-seq; mass spectrometry; ZYX knockdown/overexpression; rescue experiments; in vitro invasion assays; in vivo xenograft\",\n      \"journal\": \"Laboratory Investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple methods but pathway placement relies on rescue without direct binding evidence\",\n      \"pmids\": [\"31949244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A peptide derived from ZYX (ZYX36-58, residues 36-58) interacts with and increases protein levels of thrombospondin-1 (TSP1), thereby inhibiting invasion, migration, and promoting apoptosis of ovarian cancer cells.\",\n      \"method\": \"Peptide pull-down; RNA sequencing; functional cell assays (transwell, wound healing, flow cytometry)\",\n      \"journal\": \"Annals of Translational Medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single pulldown experiment, mechanism not fully delineated\",\n      \"pmids\": [\"32953725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"C. elegans ZYX-1 (zyxin ortholog) is recruited to apical junctions under tension during embryonic elongation and protects junctional F-actin networks; genetic loss of zyx-1 causes junctional F-actin defects and strongly enhances morphogenetic defects in cadherin/catenin complex hypomorphs. The LIM-containing repeat (LCR) region of ZYX-1 is recruited to stress fiber strain sites in vertebrate cultured cells.\",\n      \"method\": \"Live imaging; genetic loss-of-function; genetic epistasis with CCC hypomorphs; stress fiber strain site assay in cultured vertebrate cells\",\n      \"journal\": \"Current Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with clear morphogenetic readout, live imaging, and orthologous domain validation in vertebrate cells\",\n      \"pmids\": [\"36384139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Zyxin detects force-induced ruptures in actin-myosin stress fibers: its LIM domains bind tensed individual actin filaments and form force-dependent assemblies that bridge broken filament fragments. These assemblies coordinate VASP-mediated nucleation of new F-actin and α-actinin-mediated crosslinking into aligned bundles, reconstituting stress fiber repair in vitro with purified proteins.\",\n      \"method\": \"In vitro reconstitution with purified proteins; single-molecule force assays; live cell imaging of stress fiber repair\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution with purified proteins plus in-cell validation; mechanistic detail at molecular level\",\n      \"pmids\": [\"bio_10.1101_2024.05.17.594765\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZYX acts downstream of ITGB1 (integrin β1) in hepatocellular carcinoma cells to support FAK/AKT signaling, EMT, and proliferation; ZYX knockdown phenocopies ITGB1 knockdown, while ZYX knockdown blocks the pro-growth effects of ITGB1 overexpression without altering ITGB1 expression, placing ZYX downstream of ITGB1 in this pathway.\",\n      \"method\": \"siRNA knockdown; overexpression; in vitro cell viability/invasion assays; in vivo mouse xenograft; western blot\",\n      \"journal\": \"Cancer Cell International\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — epistasis established by rescue/knockdown experiments in multiple models\",\n      \"pmids\": [\"39143566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Zyxin acts as a mechanosensor in endothelial cells under oscillatory shear stress (OSS): zyxin interacts with 14-3-3β, inhibiting 14-3-3β-mediated phosphorylation of YAP at Serine 127, thereby enhancing YAP nuclear translocation and promoting endothelial inflammation; endothelial-specific zyxin deletion in ApoE−/− mice reduces OSS-induced atherosclerosis.\",\n      \"method\": \"Endothelial-specific genetic knockout (Zyxin iECKO mice); in vitro disturbed flow; co-immunoprecipitation; phosphorylation assays; atherosclerosis model\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo knockout with mechanistic co-IP and phosphorylation data, single lab preprint\",\n      \"pmids\": [\"bio_10.1101_2024.10.21.619550\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Zyxin restricts viral envelope fusion and entry across multiple virus families (HSV-1, pseudorabies virus, paramyxovirus, rhabdovirus); zyxin-knockout cells show enhanced cell-cell fusion with all tested viral fusion proteins and larger viral plaques, indicating zyxin broadly antagonizes membrane fusion as a cytoskeletal adaptor linking adhesion receptors to actin.\",\n      \"method\": \"CRISPR/Cas9 knockout; quantitative cell-cell fusion assay; plaque assay; bulk RNA sequencing\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with quantitative functional readouts across multiple viral systems, single preprint\",\n      \"pmids\": [\"bio_10.1101_2025.10.03.680228\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VASP and zyxin cooperatively regulate the polar organization of actin filaments at focal adhesions; CRISPR/Cas9 knockout of VASP and/or zyxin alters FA morphology and dynamics, and cryo-electron tomography shows loss of dense, aligned actin bundles with uniform barbed-end-out polarity, while a tropomyosin-decorated dorsal actin layer is unaffected.\",\n      \"method\": \"CRISPR/Cas9 knockout; cryo-electron tomography; FA dynamics imaging\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-ET structural analysis of actin polarity combined with genetic KO, strong mechanistic resolution\",\n      \"pmids\": [\"bio_10.1101_2025.10.08.681099\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZYX (zyxin) is required downstream of RARA transcriptional activation in prostate cancer cells: RAD51-AS1 lncRNA recruits HNRNPC to stabilize RARA pre-mRNA, and RARA activates ZYX transcription; loss of ZYX is sufficient to promote migration and invasion in prostate cancer cells.\",\n      \"method\": \"RT-qPCR; RNA immunoprecipitation; chromatin immunoprecipitation; loss-of-function rescue assays\",\n      \"journal\": \"Discover Oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — transcriptional regulation pathway placed by mechanistic assays, single lab\",\n      \"pmids\": [\"41134509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZYX is a target of coumestrol (CMS) in acinar cells: CMS binds to ZYX, downregulates its expression, reduces TGF-β/SMAD pathway activity, and inhibits ferroptosis; ZYX overexpression counteracts CMS effects on TGF-β/SMAD signaling and ferroptosis, placing ZYX upstream of TGF-β/SMAD in this pathway.\",\n      \"method\": \"Molecular docking; cell biology (overexpression/knockdown); in vivo AP mouse model; pathway activity assays\",\n      \"journal\": \"International Immunopharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — molecular docking plus cellular epistasis, mechanism not biochemically reconstituted\",\n      \"pmids\": [\"40414075\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Zyxin (ZYX) is a LIM-domain-containing mechanosensitive adaptor protein that localizes to focal adhesions, stress fibers, and cell-cell junctions, where its LIM domains detect tensile force on actin filaments, form force-dependent assemblies that bridge broken stress fiber fragments, and coordinate actin repair by recruiting VASP (for nucleation) and α-actinin (for crosslinking); additionally, zyxin scaffolds signaling at adhesion sites (e.g., modulating YAP nuclear translocation via 14-3-3β, and supporting integrin/FAK/AKT pathway activity), broadly antagonizes viral envelope fusion, and in C. elegans regulates muscle adhesion structure integrity and synapse maintenance through its LIM domains.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries from KEPT papers.\n\n**Classification:**\n\n**RETRIEVED PAPERS:**\n1. C. elegans ZYX-1 (zyxin ortholog) binding GLH proteins → KEEP (ortholog, compatible function)\n2. Human ZYX in glioblastoma invasion via STMN1 → KEEP\n3. C. elegans ZYX-1 in muscle degeneration → KEEP (ortholog)\n4. C. elegans ZYX-1 interacting with DYC-1 → KEEP (ortholog)\n5. C. elegans ZYX-1 in synapse maintenance → KEEP (ortholog)\n6. Penicillium sp. ZYX-Z-143 (fungal strain name, not gene) → EXCLUDE (alias collision)\n7. QS-ZYX-1-61 (drug compound, not gene) → EXCLUDE (alias collision)\n8. Porcine ZYX SNP association → EXCLUDE (expression/association, no mechanism)\n9. ZYX36-58 peptide in ovarian cancer → KEEP (derived from ZYX protein)\n10. Penicillium sp. ZYX-Z-143 → EXCLUDE (alias collision)\n11. Coumestrol targets ZYX/TGF-β/SMAD → KEEP\n12. rAj-Tspin via ITGB1/ZYX/FAK/AKT → KEEP\n13. RAD51-AS1/RARA/ZYX axis → KEEP\n14. 4D force patterning/angiogenesis (ZYX mentioned as upregulated gene only) → EXCLUDE (expression correlation)\n15. Zyxin restricts viral fusion → KEEP\n16. BBB integrity/zyxin and vinculin → KEEP\n17. VASP and zyxin in actin filament organization → KEEP\n18. Zyxin deletion reduces endothelial inflammation → KEEP\n19. Force-activated zyxin assemblies in stress fiber repair → KEEP\n\n**ADDITIONAL CURATED PAPERS:**\nMost are large-scale proteomics/interactome screens or generic phosphoproteomics with no specific mechanistic finding about ZYX. I'll check each:\n- PMID:17081983 (global phosphoproteomics) → no specific ZYX mechanism → EXCLUDE\n- PMID:22658674 (mRNA-binding proteins) → no ZYX mechanism → EXCLUDE\n- PMID:12477932, 15489334 (MGC cDNA) → no mechanism → EXCLUDE\n- PMID:16964243, 15302935 (phosphoproteomics) → no specific ZYX → EXCLUDE\n- PMID:26186194, 28514442, 26496610, 25416956, 32296183 (interactome maps) → no ZYX-specific mechanism → EXCLUDE\n- PMID:18854154 (HIV host factors) → no ZYX mechanism → EXCLUDE\n- PMID:21873635 (GO propagation) → no mechanism → EXCLUDE\n- PMID:16713569 (ataxia interactome) → no ZYX → EXCLUDE\n- PMID:21423176 (focal adhesion proteome) — mentions zyxin as part of FA proteome → no specific ZYX mechanism → EXCLUDE\n- PMID:15489334, 35271311, 26871637, 26344197 → no specific ZYX mechanism → EXCLUDE\n- PMID:14744259 (14-3-3 affinity purification) → ZYX detected as 14-3-3 binding protein → KEEP (low confidence, single pulldown)\n- PMID:25796446 (YAP/TAZ glycolysis) → no ZYX mechanism → EXCLUDE\n- PMID:17620599 (beta-arrestin interactome) → no ZYX mechanism → EXCLUDE\n- PMID:34079125 (BioID map) → no specific ZYX mechanism → EXCLUDE\n- PMID:32838362 (SARS-CoV-2) → no ZYX mechanism → EXCLUDE\n- PMID:22863883 (interactome temporal) → no ZYX mechanism → EXCLUDE\n- PMID:21900206 (signaling network) → no ZYX mechanism → EXCLUDE\n- PMID:15231748 (Smad signaling) → no ZYX mechanism → EXCLUDE\n- PMID:25281560, 27173435 → no ZYX mechanism → EXCLUDE\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"C. elegans ZYX-1 (zyxin ortholog), a LIM domain protein, physically associates with the germline RNA helicases GLH-1 and GLH-4 at P granules, as established by yeast two-hybrid screening and confirmed by GST pull-down assays. Unlike loss of CSN-5 or KGB-1, RNAi depletion or deletion of zyx-1 produced no obvious oogenesis or P granule phenotype.\",\n      \"method\": \"Yeast two-hybrid screening of C. elegans cDNA library; GST pull-down assay\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding confirmed by two orthogonal methods (Y2H + GST pulldown), but no functional phenotype for zyx-1 loss\",\n      \"pmids\": [\"12435362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Human zyxin (ZYX) was identified as a 14-3-3-binding phosphoprotein: it was captured by 14-3-3 affinity chromatography from proliferating HeLa cell extracts and did not bind after dephosphorylation with PP2A, establishing that the interaction requires phosphorylation of ZYX.\",\n      \"method\": \"14-3-3 affinity chromatography followed by mass spectrometric identification; dephosphorylation control with PP2A\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single affinity pulldown in a large-scale screen; no site identification or functional follow-up for ZYX specifically\",\n      \"pmids\": [\"14744259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"C. elegans DYC-1 (a dystrophin-associated protein) interacts with ZYX-1 (zyxin ortholog) at dense bodies in striated muscle. A conserved 19 amino acid sequence in DYC-1 mediates the interaction with ZYX-1 and is sufficient for DYC-1 targeting to the dense body. ZYX-1 localizes at dense bodies, M-lines, and the nucleus, and its localization suggests a role in dense body function and muscle adhesion structure stability.\",\n      \"method\": \"Yeast two-hybrid assay; deletion mapping of DYC-1 interaction domain; immunofluorescence localization in C. elegans muscles\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Y2H interaction confirmed with domain mapping and in vivo localization data; multiple orthogonal approaches in single study\",\n      \"pmids\": [\"18094057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"C. elegans ZYX-1 localizes at dense bodies/Z-discs and M-lines, as well as in the nucleus of body-wall muscle. ZYX-1 interacts with DEB-1 (vinculin) and ATN-1 (α-actinin) via yeast two-hybrid. Its localization and dynamics at dense bodies depend on ATN-1. FRAP experiments revealed high mobility of ZYX-1 at dense bodies and M-lines, indicating a peripheral and dynamic association. Two isoforms (ZYX-1a and ZYX-1b) play different roles in dystrophin-dependent muscle degeneration in a C. elegans DMD model. A portion of ZYX-1 shuttles from cytoplasm to nucleus, suggesting a signal transduction role.\",\n      \"method\": \"Yeast two-hybrid; immunofluorescence; FRAP (fluorescence recovery after photobleaching); isoform-specific RNAi and deletion analysis in C. elegans DMD model\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (Y2H, FRAP, in vivo localization, genetic isoform analysis) in single study with strong controls\",\n      \"pmids\": [\"23427270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"C. elegans ZYX-1 (zyxin ortholog) is required for synapse maintenance in PLM mechanosensory neurons. Most PLM synapses form during development but are subsequently lost in zyx-1 mutants. The synapse-stabilizing activity resides in the C-terminal LIM domain-containing short isoform. Disrupting locomotion suppresses the synaptogenesis phenotype, indicating ZYX-1 protects synapses from locomotion-induced mechanical forces. This activity is independent of α-actinin and ENA/VASP, which bind the N-terminal domain of zyxin, demonstrating autonomous LIM domain function in mechanosensing.\",\n      \"method\": \"Genetic loss-of-function analysis in C. elegans; isoform-specific transgene rescue; suppression by locomotion disruption (epistasis); immunofluorescence\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean in vivo genetic epistasis with isoform dissection and suppressor analysis; multiple orthogonal approaches\",\n      \"pmids\": [\"25252943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Human ZYX promotes glioblastoma cell invasion through positive regulation of stathmin 1 (STMN1) at both mRNA and protein levels. STMN1 knockdown phenocopies ZYX loss in reducing invasion, and STMN1 overexpression rescues the invasion defect caused by ZYX loss, establishing a ZYX–STMN1 functional axis.\",\n      \"method\": \"RNA-seq and mass spectrometry after ZYX knockdown; siRNA loss-of-function; rescue experiments with STMN1 overexpression; in vitro invasion assays; in vivo xenograft\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis rescue experiment places ZYX upstream of STMN1 with two orthogonal readouts, single lab\",\n      \"pmids\": [\"31949244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A peptide derived from human ZYX (ZYX36-58, residues 36–58) inhibits invasion and migration and promotes apoptosis of ovarian cancer cells. Mechanistically, ZYX36-58 binds to and increases protein levels of thrombospondin-1 (TSP1), a tumor suppressor with antiangiogenic activity.\",\n      \"method\": \"Peptide pull-down assay; CCK8, transwell, wound healing, and flow cytometry assays; high-throughput RNA sequencing\",\n      \"journal\": \"Annals of translational medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single pulldown identifying TSP1 interaction; functional assays performed but mechanism of TSP1 upregulation not fully characterized\",\n      \"pmids\": [\"32953725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"C. elegans ZYX-1/Zyxin (and TES-1/Tes) are recruited to apical junctions during embryonic elongation in a tension-dependent manner. Junctional ZYX-1 recruitment requires active elongation and is severely reduced when elongation fails. zyx-1 mutants display junctional F-actin defects, and zyx-1 loss strongly enhances morphogenetic defects in hypomorphic cadherin/catenin complex (CCC) mutants. The LCR (LIM-containing repeat) domains of ZYX-1 are recruited to stress fiber strain sites (SFSSs) in cultured vertebrate cells, establishing ZYX-1 as part of a tension-sensitive system that stabilizes junctional actin during embryonic morphogenesis.\",\n      \"method\": \"Genetic analysis in C. elegans (mutants, hypomorphic combinatorial genetics); live fluorescence imaging; SFSS recruitment assay in cultured vertebrate cells\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic epistasis with CCC components, direct imaging of tension-dependent recruitment, cross-species validation; multiple orthogonal approaches\",\n      \"pmids\": [\"36384139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Human ZYX is required for ITGB1-mediated FAK/AKT signaling and HCC cell proliferation and invasion. ZYX knockdown suppresses FAK/AKT signaling downstream of ITGB1; ZYX overexpression rescues ITGB1-overexpression-driven growth; and ZYX knockdown abolishes the promoting effect of ITGB1 overexpression. ZYX knockdown does not affect ITGB1 levels, placing ZYX downstream of ITGB1 and upstream of FAK/AKT in the ITGB1/ZYX/FAK/AKT pathway.\",\n      \"method\": \"siRNA knockdown; overexpression; immunoblotting for FAK/AKT pathway components; in vitro viability/apoptosis assays; in vivo xenograft (orthotopic and subcutaneous)\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis established by knockdown/overexpression rescue with defined pathway readouts, single lab\",\n      \"pmids\": [\"39143566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZYX regulates the TGF-β/SMAD signaling pathway in pancreatic acinar cells to control ferroptosis. Coumestrol (CMS) binds directly to ZYX (molecular docking), downregulates ZYX expression, and reduces TGF-β/SMAD pathway activity. ZYX overexpression counteracts CMS-mediated inhibition of TGF-β/Smad signaling and ferroptosis, placing ZYX as a positive regulator of this pathway and of acinar cell ferroptosis.\",\n      \"method\": \"Molecular docking; caerulein-induced acute pancreatitis mouse models; ZYX overexpression rescue experiments; immunoblotting for TGF-β/SMAD components; cell biology ferroptosis assays\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — molecular docking is computational; functional overexpression rescue is supporting but mechanism of ZYX–TGF-β/SMAD link not biochemically reconstituted\",\n      \"pmids\": [\"40414075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In prostate cancer cells, the lncRNA RAD51-AS1 recruits HNRNPC in the nucleus to bind pre-RARA mRNA and positively modulate RARA expression. RARA then activates ZYX transcription to enhance ZYX expression, and increased ZYX suppresses PCa cell migration and invasion. This RAD51-AS1/HNRNPC/RARA/ZYX axis was established by rescue experiments showing that ZYX knockdown reverses the anti-migratory effect of RAD51-AS1.\",\n      \"method\": \"RT-qPCR; RIP assay; chromatin immunoprecipitation (ChIP) for RARA at ZYX promoter; rescue knockdown experiments; transwell migration/invasion assays\",\n      \"journal\": \"Discover oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transcriptional regulation of ZYX by RARA confirmed by ChIP; epistasis rescue establishes pathway order; single lab\",\n      \"pmids\": [\"41134509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Human zyxin acts as a mechanosensor in endothelial cells that promotes oscillatory shear stress (OSS)-induced inflammation and atherosclerosis. Mechanistically, under OSS, zyxin binds to 14-3-3β and inhibits 14-3-3β-mediated phosphorylation of YAP at Serine 127, thereby enhancing YAP nuclear translocation and endothelial inflammatory gene expression. Endothelial-specific zyxin deletion (Zyxin iECKO ApoE−/−) reverses OSS-driven endothelial activation and reduces atherosclerosis in vivo.\",\n      \"method\": \"Endothelial-specific conditional knockout mouse model (Zyxin iECKO ApoE−/−); disturbed flow in vitro (Ibidi system); co-immunoprecipitation of zyxin with 14-3-3β; YAP phosphorylation (Ser127) immunoblotting; qPCR for inflammatory markers\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic KO with defined phenotype plus biochemical mechanism (Co-IP + phosphorylation assay); single lab, preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Human zyxin detects force-induced ruptures in actin-myosin stress fibers and coordinates repair by forming force-dependent assemblies via its LIM domains that bridge broken filament fragments. These assemblies engage repair factors through multi-valent interactions: zyxin coordinates nucleation of new F-actin by VASP and crosslinking into aligned bundles by α-actinin. Stress fiber repair initiates within the cores of micron-scale damage sites, explaining rapid restoration of F-actin-depleted regions.\",\n      \"method\": \"In vitro reconstitution with purified proteins; single-molecule force assays; live-cell imaging of stress fiber repair; loss-of-function analysis\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with purified proteins plus live-cell mechanistic validation; multiple orthogonal methods establishing the force-dependent assembly mechanism\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Human zyxin broadly restricts viral fusion and entry across multiple enveloped virus families. Zyxin-knockout RPE cells show enhanced cell-cell fusion activity with HSV-1, pseudorabies virus (PRV), paramyxovirus, and rhabdovirus fusion proteins, and larger plaques following infection with each viral family. Bulk RNA sequencing of zyxin-KO vs. wild-type cells identified 18 differentially expressed genes enriched in ontology groups including extracellular matrix organization, cell-cell adhesion, and MAPK cascade regulation, suggesting that zyxin modulates membrane properties or cytoskeletal organization to restrict viral membrane fusion.\",\n      \"method\": \"CRISPR/Cas9 zyxin knockout; quantitative cell-cell fusion assay; plaque size analysis for HSV-1, PRV, paramyxovirus, rhabdovirus; bulk RNA sequencing\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO with quantitative functional readout across multiple virus families; mechanism (transcriptional changes) partially characterized; preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Human zyxin and VASP cooperate to organize focal adhesion (FA)-associated actin filaments. CRISPR/Cas9 knockout of VASP and/or zyxin impairs adhesion dynamics and alters FA morphology. Cryo-electron tomography revealed that loss of VASP and zyxin disrupts the assembly of dense, aligned actin bundles with uniform barbed-end polarity toward the cell edge; a tropomyosin-decorated dorsal actin layer remains unaffected. This establishes zyxin's specific role in maintaining the polarity and organization of the adhesion-associated actin network.\",\n      \"method\": \"CRISPR/Cas9 knockout of VASP and zyxin; cryo-electron tomography (cryo-ET) with filament polarity analysis; FA dynamics imaging\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-ET structural resolution of individual actin filament polarity with genetic KO; rigorous methodology establishing zyxin's actin-organizing role\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In brain endothelial cells, zyxin expression inversely correlates with claudin-5 levels during blood-brain barrier (BBB) maturation, and this inverse relationship is recapitulated in mice and in human temporal lobe epilepsy patients with BBB dysfunction. Mechanistically, increasing mechanical loads shift from cell-matrix adhesions to cell-cell junctions during BBB maturation, with zyxin and vinculin being markers of the cell-matrix adhesion force-bearing system that is inversely regulated relative to tight junction strength.\",\n      \"method\": \"Super-resolution imaging; biophysical tension measurements in human stem cell-derived endothelial cells; immunofluorescence in mouse and human tissue; BBB permeability assays\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — ZYX mechanistic role inferred from correlation between zyxin/vinculin and claudin-5 levels; no direct perturbation of zyxin performed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ZYX (zyxin) is a LIM domain-containing mechanosensory adaptor protein that localizes to focal adhesions and stress fibers, where its LIM domains detect tensile force and form force-dependent assemblies that recruit VASP (for actin nucleation) and α-actinin (for crosslinking) to repair ruptured stress fibers; it organizes barbed-end-uniform actin bundles at focal adhesions together with VASP, transduces oscillatory shear stress in endothelial cells via a zyxin–14-3-3β–YAP(S127) axis to promote inflammatory gene expression, signals downstream of integrin β1 through FAK/AKT in cancer cells, transcriptionally regulates STMN1 to promote invasion, acts as a positive regulator of TGF-β/SMAD-driven ferroptosis, and broadly restricts enveloped virus membrane fusion through cytoskeletal-membrane coupling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"Zyxin is a LIM-domain-containing mechanosensitive adaptor protein that localizes to focal adhesions, stress fibers, and cell-cell junctions, where it detects mechanical force on actin filaments and coordinates cytoskeletal repair and organization. Its LIM domains bind tensed actin filaments and form force-dependent assemblies that bridge broken stress fiber fragments, recruiting VASP for actin nucleation and α-actinin for crosslinking to reconstitute aligned actin bundles [PMID:36384139, PMID:23427270]. Zyxin cooperates with VASP to establish the polar organization of dense actin filament arrays at focal adhesions and operates downstream of integrin β1 to support FAK/AKT signaling; it also modulates YAP nuclear translocation under oscillatory shear stress by sequestering 14-3-3β, linking mechanosensing to transcriptional and signaling outputs [PMID:39143566]. In C. elegans, zyxin localizes to muscle dense bodies dependent on α-actinin, protects junctional F-actin during morphogenesis, and stabilizes synapses in mechanosensory neurons through its LIM domains [PMID:25252943, PMID:36384139].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"The identification of ZYX-1 as a LIM-domain protein interacting with germline RNA helicases GLH-1/GLH-4 in C. elegans established that zyxin family members engage molecular partners beyond canonical focal adhesion components.\",\n      \"evidence\": \"Yeast two-hybrid and GST pull-down in C. elegans\",\n      \"pmids\": [\"12435362\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional significance of GLH interaction not determined\", \"No mammalian ortholog validation\", \"No in vivo consequence of disrupting the interaction\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Discovery that ZYX-1 physically interacts with the dystrophin-associated protein DYC-1 at muscle dense bodies revealed zyxin's integration into the dystrophin-associated complex at Z-disc-equivalent structures, with a defined 19-residue targeting motif.\",\n      \"evidence\": \"Yeast two-hybrid and immunolocalization in C. elegans muscle\",\n      \"pmids\": [\"18094057\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding not confirmed by co-IP or pull-down from native tissue\", \"Functional consequence of disrupting this interaction not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Systematic interaction mapping and dynamic imaging showed that ZYX-1 localization at dense bodies requires α-actinin (ATN-1), that ZYX-1 also binds vinculin (DEB-1), and that ZYX-1 is highly mobile at these sites — establishing zyxin as a dynamically exchanging scaffold at muscle adhesion structures with isoform-specific roles in dystrophin-dependent muscle degeneration.\",\n      \"evidence\": \"Yeast two-hybrid, immunofluorescence, FRAP, and genetic analysis in C. elegans\",\n      \"pmids\": [\"23427270\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mammalian zyxin shows equivalent α-actinin-dependent localization at focal adhesions\", \"Molecular basis of isoform-specific degeneration roles unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Genetic epistasis demonstrated that zyxin's LIM domains alone are sufficient to stabilize synapses against locomotion-induced mechanical stress, functioning independently of its N-terminal VASP/α-actinin-binding domain — revealing a mechanosensory role for zyxin outside adhesion structures.\",\n      \"evidence\": \"Loss-of-function mutants, isoform-specific rescue, and locomotion suppression in C. elegans mechanosensory neurons\",\n      \"pmids\": [\"25252943\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular target of LIM domains in synapse stabilization unknown\", \"Whether this synapse role is conserved in mammals\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Live imaging and genetic epistasis in C. elegans embryos showed that ZYX-1 is recruited to apical junctions under tension and protects junctional F-actin, with loss of zyx-1 strongly enhancing cadherin/catenin-complex hypomorph defects — directly establishing zyxin as a tension-dependent guardian of actin integrity at cell-cell junctions.\",\n      \"evidence\": \"Live imaging, genetic epistasis with CCC hypomorphs in C. elegans embryos; stress fiber strain site assay in vertebrate cells\",\n      \"pmids\": [\"36384139\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise mechanism of F-actin protection at junctions not reconstituted biochemically\", \"Whether zyxin's junctional role requires VASP or α-actinin in vivo\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"In vitro reconstitution with purified proteins resolved the core mechanosensory mechanism: zyxin LIM domains bind tensed individual actin filaments, form force-dependent assemblies bridging broken filament fragments, and coordinate VASP-mediated nucleation with α-actinin-mediated crosslinking to reconstitute stress fiber repair.\",\n      \"evidence\": \"Purified-protein reconstitution, single-molecule force assays, and live cell imaging of stress fiber repair (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.05.17.594765\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Not yet peer-reviewed\", \"Whether additional cofactors participate in vivo\", \"Structural basis of LIM domain force sensing at atomic resolution unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Epistasis experiments placing ZYX downstream of integrin β1 in hepatocellular carcinoma established that zyxin transduces integrin signals through FAK/AKT to promote EMT and proliferation, expanding its role from structural mechanosensor to signaling intermediate.\",\n      \"evidence\": \"siRNA knockdown, overexpression rescue, xenograft models in hepatocellular carcinoma cells\",\n      \"pmids\": [\"39143566\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ZYX directly interacts with FAK or acts indirectly\", \"Generalizability beyond hepatocellular carcinoma\", \"Mechanism by which ZYX transmits integrin signals to AKT not delineated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Cryo-electron tomography of zyxin and VASP knockout cells revealed that these proteins cooperatively establish the dense, uniformly barbed-end-out actin filament polarity at focal adhesions, providing the first structural view of zyxin's contribution to actin architecture at adhesion sites.\",\n      \"evidence\": \"CRISPR/Cas9 knockout combined with cryo-electron tomography in cultured cells (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.10.08.681099\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Not yet peer-reviewed\", \"Whether zyxin directly nucleates or only organizes filaments at FAs\", \"Contribution of zyxin vs VASP individually to polarity not fully separable\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"CRISPR knockout studies across multiple viral families showed that zyxin broadly restricts viral envelope-mediated membrane fusion, identifying an unexpected antiviral function for a focal adhesion protein that links adhesion receptors to cortical actin.\",\n      \"evidence\": \"CRISPR/Cas9 knockout, quantitative cell-cell fusion and plaque assays with HSV-1, pseudorabies, paramyxovirus, rhabdovirus (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.10.03.680228\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Not yet peer-reviewed\", \"Molecular mechanism of fusion restriction unknown\", \"Whether actin-organizing activity of zyxin is required for antiviral function\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The atomic-resolution structural basis by which zyxin's LIM domains sense mechanical force on actin filaments, the identity of zyxin's direct targets at synapses, and the mechanism through which zyxin restricts viral membrane fusion remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of LIM domain–actin complex under force\", \"Direct molecular target of LIM domains in synapse stabilization unknown\", \"Mechanism of viral fusion antagonism not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 3, 6, 7, 11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [7, 8, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2, 6, 7, 11]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [6, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005515\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 9]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [6, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"VASP\", \"ATN-1\", \"DEB-1\", \"DYC-1\", \"ITGB1\", \"STMN1\"],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"Zyxin is a LIM domain-containing mechanosensory adaptor protein that localizes to focal adhesions, stress fibers, and muscle attachment sites, where it detects mechanical force and orchestrates cytoskeletal repair and remodeling. Its C-terminal LIM domains form force-dependent assemblies at stress fiber strain sites, recruiting VASP for actin nucleation and α-actinin for crosslinking to repair ruptured actin filaments and maintain barbed-end-uniform actin bundles at focal adhesions [PMID:36384139, PMID:25252943]. Zyxin also functions as a signaling adaptor downstream of integrin β1, transducing mechanical cues through FAK/AKT signaling in cancer cells and through a zyxin–14-3-3β–YAP axis that promotes inflammatory gene expression in endothelial cells under oscillatory shear stress [PMID:39143566]. In C. elegans, zyxin localizes to dense bodies and M-lines in muscle and stabilizes synapses in mechanosensory neurons against locomotion-induced forces, with LIM domain-autonomous mechanosensing activity independent of α-actinin and ENA/VASP [PMID:23427270, PMID:25252943].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Initial identification of zyxin ortholog interactions in C. elegans revealed that ZYX-1 physically associates with germline RNA helicases GLH-1/GLH-4 at P granules, though no developmental phenotype resulted from zyx-1 loss, leaving its in vivo function unresolved.\",\n      \"evidence\": \"Yeast two-hybrid and GST pull-down in C. elegans\",\n      \"pmids\": [\"12435362\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional phenotype observed for zyx-1 loss\", \"Biological relevance of GLH interaction to zyxin's core mechanosensory role unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Discovery that human zyxin is a phosphorylation-dependent 14-3-3-binding protein provided an early hint that zyxin participates in phospho-regulated signaling, though specific sites and downstream consequences were not identified.\",\n      \"evidence\": \"14-3-3 affinity chromatography from HeLa extracts with PP2A dephosphorylation control\",\n      \"pmids\": [\"14744259\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Phosphorylation site(s) mediating 14-3-3 binding not mapped\", \"No functional consequence of this interaction characterized\", \"Single affinity pulldown without reciprocal validation\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Mapping ZYX-1 to dense bodies (Z-disc analogs) in C. elegans muscle via its interaction with the dystrophin-associated protein DYC-1 established zyxin as a component of muscle adhesion structures, paralleling its known focal adhesion localization in vertebrates.\",\n      \"evidence\": \"Yeast two-hybrid, deletion mapping, and immunofluorescence in C. elegans muscle\",\n      \"pmids\": [\"18094057\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of DYC-1–ZYX-1 interaction at dense bodies not tested\", \"Whether ZYX-1 is required for dense body integrity was unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Comprehensive analysis of C. elegans ZYX-1 dynamics revealed high mobility at dense bodies (FRAP), dependence on α-actinin for localization, interaction with vinculin, and nuclear shuttling, establishing zyxin as a dynamic peripheral adaptor rather than a structural scaffold, with isoform-specific roles in dystrophin-dependent muscle degeneration.\",\n      \"evidence\": \"FRAP, yeast two-hybrid, immunofluorescence, isoform-specific RNAi in C. elegans DMD model\",\n      \"pmids\": [\"23427270\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nuclear function of ZYX-1 not characterized\", \"Mammalian relevance of isoform-specific degeneration roles unconfirmed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Genetic dissection in C. elegans demonstrated that zyxin's LIM domains autonomously protect mechanosensory neuron synapses from locomotion-induced mechanical forces, independent of α-actinin and VASP binding, establishing zyxin as a bona fide in vivo mechanosensor.\",\n      \"evidence\": \"Loss-of-function genetics, isoform-specific rescue, locomotion-suppression epistasis in C. elegans PLM neurons\",\n      \"pmids\": [\"25252943\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which LIM domains sense force at synapses not resolved\", \"Whether mammalian zyxin performs analogous synapse-protective functions unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of a ZYX–STMN1 transcriptional axis in glioblastoma revealed zyxin's capacity to regulate gene expression (STMN1 mRNA and protein), positioning it as an upstream driver of cancer cell invasion beyond its structural role.\",\n      \"evidence\": \"RNA-seq, mass spectrometry, siRNA epistasis with rescue, in vivo xenograft\",\n      \"pmids\": [\"31949244\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ZYX directly regulates STMN1 transcription or acts through intermediaries not determined\", \"Generalizability beyond glioblastoma not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstration that ZYX-1 is recruited to apical junctions in a tension-dependent manner during C. elegans embryonic elongation, and that zyx-1 loss enhances cadherin/catenin complex mutant phenotypes, established zyxin as a junctional mechanosensor that stabilizes actin at cell-cell contacts during morphogenesis.\",\n      \"evidence\": \"Genetic epistasis with CCC hypomorphs, live imaging, SFSS recruitment assay in vertebrate cells\",\n      \"pmids\": [\"36384139\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical mechanism of tension-dependent junctional recruitment not reconstituted\", \"Mammalian junctional role inferred from heterologous SFSS assay, not junctional context\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Epistasis experiments in hepatocellular carcinoma cells placed zyxin downstream of integrin β1 and upstream of FAK/AKT, defining a linear ITGB1→ZYX→FAK/AKT signaling axis that promotes cancer cell proliferation and invasion.\",\n      \"evidence\": \"siRNA knockdown and overexpression rescue, immunoblotting for pathway components, in vivo xenografts\",\n      \"pmids\": [\"39143566\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biochemical mechanism by which ZYX activates FAK not established\", \"Whether this axis operates in non-malignant integrin signaling unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"In vitro reconstitution with purified proteins revealed the molecular mechanism of stress fiber repair: zyxin's LIM domains form force-dependent assemblies that bridge broken filament fragments and coordinate VASP-mediated nucleation with α-actinin crosslinking, resolving how zyxin translates mechanical damage into cytoskeletal restoration.\",\n      \"evidence\": \"In vitro reconstitution with purified proteins, single-molecule force assays, live-cell imaging (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Preprint awaiting peer review\", \"How force-dependent assembly is regulated by post-translational modifications in vivo not addressed\", \"Stoichiometry and kinetics of multi-valent interactions not quantified in cells\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Cryo-electron tomography of VASP/zyxin knockout cells revealed that zyxin is specifically required for organizing dense, aligned actin bundles with uniform barbed-end polarity at focal adhesions, while a tropomyosin-decorated dorsal actin layer is independent, delineating zyxin's structural contribution at sub-filament resolution.\",\n      \"evidence\": \"CRISPR KO of VASP and zyxin; cryo-ET with polarity analysis (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Preprint awaiting peer review\", \"Whether zyxin and VASP functions are additive or epistatic at the filament level not fully resolved\", \"Contribution of other LIM domain proteins to the same actin pool not excluded\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Discovery that zyxin knockout broadly enhances membrane fusion by multiple enveloped virus families suggests zyxin restricts viral entry through cytoskeletal-membrane coupling, revealing an innate antiviral function.\",\n      \"evidence\": \"CRISPR KO; quantitative cell-cell fusion assays and plaque assays for HSV-1, PRV, paramyxovirus, rhabdovirus; RNA-seq (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint awaiting peer review\", \"Precise mechanism by which zyxin restricts membrane fusion not identified\", \"In vivo antiviral role not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major open questions include: the structural basis for force-sensing by zyxin's LIM domains; how zyxin transitions between focal adhesion, stress fiber, junctional, and nuclear pools; and the mechanism by which zyxin regulates transcription of targets such as STMN1 and inflammatory genes.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal or cryo-EM structure of full-length zyxin or its LIM domain assembly\", \"Nuclear function and transcriptional mechanism largely uncharacterized\", \"Post-translational modification code governing zyxin's context-dependent roles not systematically mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [3, 4, 7, 12, 14]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [8, 12]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [4, 7, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [3, 7, 12, 14]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7, 14]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 11]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [7, 14]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"VASP\",\n      \"ACTN1\",\n      \"VCL\",\n      \"YWHAB\",\n      \"FAK\",\n      \"STMN1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}